The CXC chemokines that possess the receptor-signaling glutamic acid-leucine-arginine (ELR) motif (e.g., CXCL1/GROα, CXCL8/IL-8; ref. 1) are important to the influx of inflammatory cells that mediates much of the pathology in multiple settings, including ischemia-reperfusion injury (ref. 2, 3), endotoxemia-induced acute respiratory distress syndrome (ARDS; ref. 4), arthritis, and immune complex-type glomerulonephritis (ref. 5). For instance, inappropriately released hydrolytic enzymes and reactive oxygen species from activated neutrophils initiate and/or perpetuate the pathologic processes. On the other hand, during most bacterial infections this chemokine response represents a critical first line of defense, but even here ELR+ CXC chemokine responses can, via their abilities to activate inflammatory cells displaying the CXCR1 and CXCR2 receptors, exacerbate the pathology. For example, during experimental ‘cecal puncture and ligation’ sepsis, neutralization of MIP-2 reduces mouse mortality from 85 to 38% (ref. 6). Infect. Immun. 65:3847–3851). And experimental treatments that eliminate circulating neutrophils ameliorate the pathology of pneumonic mannheimiosis (ref. 7), wherein CXCL8 expression in the airways variably effects the neutrophil chemoattraction (ref. 8, 9). Despite the critical importance of these chemokine responses in many settings, wayward inflammatory cell responses are sufficiently damaging that the development of therapeutic tools with which we can block ELR+ chemokines has become a research priority (ref. 10).
The ‘ELR’ chemokines chemoattract and activate inflammatory cells via their CXCR1 and CXCR2 receptors (ref. 1, 11). The CXCR1 is specific for CXCL8 and CXCL6/granulocyte chemotactic protein-2 (GCP-2), while the CXCR2 binds CXCL8 with high affinity, but also macrophage inflammatory protein-2 (MIP-2), CXCL1, CXCL5/ENA-78, and CXCL6 with somewhat lower affinities (see, for example, ref. 10). CXCL8 signaling in cell lines transfected with the human CXCR1 or CXCR2 induces equipotent chemotactic responses (ref. 13, 14), and while neutrophil cytosolic free Ca++ changes and cellular degranulation in response to CXCL8 are also mediated by both receptors, the respiratory burst and activation of phospholipase D reportedly depend exclusively on the CXCR1 (ref.16). On the other hand, it has been reported that a non-peptide antagonist of the CXCR2, but not the CXCR1, antagonizes CXCL8-mediated neutrophil chemotaxis, but not cellular activation (ref. 17). Finally, there is abundant evidence that chemokines are most often redundantly expressed during inflammatory responses (see, for example, ref. 8). But, despite active research in the field, no CXC chemokine antagonists are known in the prior art that are effective in suppressing adverse inflammatory cell activity induced by either ELR-CXC chemokine receptor.